Attenuation of Ca2+ homeostasis, oxidative stress, and mitochondrial dysfunctions in diabetic rat heart: insulin therapy or aerobic exercise?

• Autor(a) principal: Natali, Antônio J.
• Data de Publicação: 2015
• Outros Autores: Silva, Márcia F. da, Silva, Edson da, Gomes, Gilton J., Teodoro, Bruno G., Cunha, Daise N. Q., Drummond, Lucas R., Drummond, Filipe R., Moura, Anselmo G., Belfort, Felipe G., Oliveira, Alessandro de, Maldonado, Izabel R. S. C., Alberici, Luciane C.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: LOCUS Repositório Institucional da UFV
• Texto Completo: https://doi.org/10.1152/japplphysiol.00915.2014; http://www.locus.ufv.br/handle/123456789/19620
• topic: Diabetes mellitus; Mitochondria; Nox-4

We tested the effects of swimming training and insulin therapy, either alone or in combination, on the intracellular calcium ([Ca2+]i) homeostasis, oxidative stress, and mitochondrial functions in diabetic rat hearts. Male Wistar rats were separated into control, diabetic, or diabetic plus insulin groups. Type 1 diabetes mellitus was induced by streptozotocin (STZ). Insulin-treated groups received 1 to 4 UI of insulin daily for 8 wk. Each group was divided into sedentary or exercised rats. Trained groups were submitted to swimming (90 min/day, 5 days/wk, 8 wk). [Ca2+]i transient in left ventricular myocytes (LVM), oxidative stress in LV tissue, and mitochondrial functions in the heart were assessed. Diabetes reduced the amplitude and prolonged the times to peak and to half decay of the [Ca2+]i transient in LVM, increased NADPH oxidase-4 (Nox-4) expression, decreased superoxide dismutase (SOD), and increased carbonyl protein contents in LV tissue. In isolated mitochondria, diabetes increased Ca2+ uptake, susceptibility to permeability transition pore (MPTP) opening, uncoupling protein-2 (UCP-2) expression, and oxygen consumption but reduced H2O2 release. Swimming training corrected the time course of the [Ca2+]i transient, UCP-2 expression, and mitochondrial Ca2+ uptake. Insulin replacement further normalized [Ca2+]i transient amplitude, Nox-4 expression, and carbonyl content. Alongside these benefits, the combination of both therapies restored the LV tissue SOD and mitochondrial O2 consumption, H2O2 release, and MPTP opening. In conclusion, the combination of swimming training with insulin replacement was more effective in attenuating intracellular Ca2+ disruptions, oxidative stress, and mitochondrial dysfunctions in STZ-induced diabetic rat hearts. diabetic cardiomyopathy leads initially to diastolic dysfunction, which frequently progresses to heart failure and sudden death (12). Cardiac systolic and diastolic dysfunctions are associated with impaired intracellular calcium (Ca2+) homeostasis (16, 23, 43, 48) attributable to decreased expression and/or activity of Ca2+ regulatory proteins (10, 16, 23, 43, 47, 48). Heart failure induced by diabetes is also associated with increased reactive oxygen species (ROS) (19) as well as with NADPH oxidase (Nox) activation by glycated proteins and mitochondrial dysfunction (47). Mitochondrial dysfunctions in diabetic hearts are related with increased expression of mitochondrial uncoupling protein-3 (UCP-3) (8, 19, 44), impaired respiratory capacity, altered expression of respiratory chain complexes (8) and Ca2+ uptake, higher susceptibility to mitochondrial permeability transition pore (MPTP) opening, and elevated apoptotic signaling molecules (8, 26). Recently, it has been demonstrated that in diabetic hearts the expression of phosphorylated Ca2+/calmodulin-dependent protein kinase II (CaMKII) and Nox was augmented, and its activation by impaired Ca2+ metabolism increases ROS production (32). Aerobic exercise and insulin replacement are strategies to manage diabetes (41, 46). Endurance exercise training was shown to improve cardiomyocyte Ca2+ cycling and restore its intracellular calcium ([Ca2+]i) transient and hence contractile function in diabetic rats (41). Endurance exercise is also known to protect the rat myocardium against oxidative stress (22). The stimulation of Ca2+ uptake by insulin replacement is involved in the regulation of heart metabolism and transporter activities (34). However, the effects of combined endurance exercise training and insulin treatment on cardiac oxidative stress and heart mitochondrial function of diabetic rats are poorly understood. This study sought to examine the effects of swimming training combined with insulin treatment on cardiac oxidative stress and mitochondrial dysfunctions in streptozotocin (STZ)-induced diabetic rats.